Cannabidiol inhibits angiogenesis by multiple mechanisms

Abstract

BACKGROUND AND PURPOSE Several studies have demonstrated anti‐proliferative and pro‐apoptotic actions of cannabinoids on various tumours, together with their anti‐angiogenic properties. The non‐psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down‐regulates some pro‐angiogenic signals produced by glioma cells. As its anti‐angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. EXPERIMENTAL APPROACH Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability – through [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] assay and FACS analysis – and in vitro motility – both in a classical Boyden chamber test and in a wound‐healing assay. We next investigated CBD effects on different angiogenesis‐related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. KEY RESULTS CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down‐modulation of several angiogenesis‐related molecules. CONCLUSIONS AND IMPLICATIONS This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy.

The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids

“…Furthermore, this group significantly reduced angiogenesis in vivo in Matrigel sponges. Key down-stream targets inhibited by CBD in HUVEC cells included MMP-2 and −9, TIMP1, plasminogen activator uPA, chemokines CXCL16 and IL-8, and growth factors enodothelin-1 and platelet derived growth factor-AA (Solinas et al, 2012). Moreover, CBD treatment led to a decrease in CD31 (vascularization marker) staining in tumor stroma in a mouse xenograft model where tumors were derived from subcutaneously implanted human lung cancer cells (Ramer et al, 2013).…”

The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model

“…These vary with each cannabinoid but generally include the induction of apoptosis and/or autophagy via engagement of the mitogen-activated protein kinase (MAPK) and the endoplasmic reticulum stress-related pathways (5,7). Cannabinoids have also been reported to be antiangiogenic (8) as well as anti-inflammatory (9). Furthermore, limited clinical trial data have reinforced the concept that THC possesses therapeutic potential.…”

Epigenetic control of skin differentiation genes by phytocannabinoids

“…The understanding of the epigenetic regulation of keratinocyte differentiation by phytocannabinoids may pave the way to the development of new drugs for skin diseases, analogous to other human disorders like multiple sclerosis (Rog, 2010), bowel disease (Lal et al, 2011) and cancer (Solinas et al, 2012).…”

“…However, the therapeutic potential of cannabinoid-based preparations for skin diseases has not yet been investigated. Up to now, just one study has reported the inhibition of human keratinocyte proliferation by phytocannabinoids, suggesting that phytocannabinoids could be beneficial in the treatment of psoriasis (Wilkinson and Williamson, 2007).In this study, we investigated the effects of three major non-psychoactive components of Cannabis sativa (Izzo et al, 2009): CBD and its precursor cannabigerol (CBG), that are, together with Δ9-tetrahydrocannbinol, the most abundant phytocannabinoids (Hill et al, 2012b); and cannabidivarin (CBDV), a propyl analogue of CBD which like its congener has anticonvulsant properties (Jones et al, 2010;Hill et al, 2012a).The understanding of the epigenetic regulation of keratinocyte differentiation by phytocannabinoids may pave the way to the development of new drugs for skin diseases, analogous to other human disorders like multiple sclerosis (Rog, 2010), bowel disease (Lal et al, 2011) and cancer (Solinas et al, 2012). …”